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Prior work in our laboratory has identified putative subtypes of δ (
δ
cx-1,
δ
cx-2,
δ
ncx-1,
δ
ncx-2) and
κ
2 (
κ
2a and
κ
2b) receptors. Previous studies showed that chronic (three day) i.c.v. administration of antisense oligodeoxynucleotide to the cloned δ opioid receptor selectively decreased [
3H][
d-Ala
2,
d-Leu
5]enkephalin binding to the
δ
ncx site, not the
δ
cx-2 site. The present study extends this work by demonstrating that δ antisense DNA selectively affects the
δ
ncx-2 site sparing the other putative δ receptor subtypes and
κ
2 receptor subtypes. This selectivity is not due to anatomically specific effects of δ antisense DNA since autoradiograms show that δ binding is reduced in all regions of the brain after chronic i.c.v. administration of δ antisense DNA. These data strongly suggest that the
δ
cx-1,
δ
cx-2,
δ
ncx-1,
κ
2a and
κ
2b binding sites are different proteins than the
δ
ncx-2 binding site, which, based on its sensitivity to δ antisense DNA, is synonymous to the cloned δ opioid receptor. Viewed collectively, these data suggest that administration of δ antisense DNA, and by extension other receptor-selective antisense DNA, is a powerful approach to distinguishing between postulated receptor subtypes.